The Friedreich’s ataxia (FRDA) therapeutic landscape has entered a new phase following the approval of Skyclarys® (omaveloxolone), the first approved treatment for the disease. At the same time, investigational approaches including frataxin replacement therapies, gene-addition strategies, and treatments targeting mitochondrial dysfunction continue to advance through development. As these programs progress, researchers need human disease models to demonstrate target engagement and functional rescue in tissues directly affected by frataxin deficiency. Because cardiac disease remains a major contributor to morbidity and mortality in FRDA, human cardiomyocyte models are becoming increasingly important for therapeutic development.^2-5

While FRDA is often viewed primarily as a neurodegenerative disease, the heart is one of the organs most affected, with cardiomyopathy as a common cause of mortality. Human iPSC-derived cardiomyocytes provide a physiologically relevant system for studying cardiac pathology. They enableing researchers to investigate disease mechanisms directly within the cell type affected by FRDA-associated cardiomyopathy.^1-4

Friedreich’s ataxia is more than a neurological disease

FRDA is an autosomal recessive disorder most commonly caused by GAA repeat expansions in the FXN gene, resulting in reduced expression of frataxin, a mitochondrial protein essential for iron-sulfur cluster biogenesis, oxidative phosphorylation, and cellular energy production. Loss of frataxin disrupts mitochondrial homeostasis, leading to impaired energy metabolism, oxidative stress, and progressive cellular dysfunction.^1,4

Although neurological symptoms define the disease clinically, cardiac involvement occurs in most patients and may include hypertrophic cardiomyopathy, ventricular remodeling, conduction abnormalities, and arrhythmias. Because the heart relies heavily on mitochondrial energy production, cardiac involvement is a prominent feature of FRDA, although disease severity and clinical presentation can vary between patients ^2-4.

Challenges of studying FRDA cardiomyopathy

Understanding FRDA cardiomyopathy has been limited by restricted access to primary human cardiac tissue and the inability of some animal models to fully reproduce human disease.

The pathology involves a complex interplay of mitochondrial dysfunction, oxidative stress, altered iron metabolism, impaired calcium homeostasis, and downstream effects on cardiac structure and function. Investigating these mechanisms requires model systems that closely reflect human cardiac biology.

Disease-relevant phenotypes that can be measured in vitro

Patient-derived iPSC cardiomyocytes have expanded the range of experimental tools available for studying FRDA-associated cardiac biology. Studies using FRDA cardiomyocyte models suggested changes in cellular pathways relevant to mitochondrial function, oxidative stress, calcium handling, electrophysiology, and contractility ^1,4.

Reported phenotypes include:

• Reduced frataxin expression
• Mitochondrial dysfunction and impaired bioenergetics
• Increased reactive oxygen species (ROS)
• Abnormal calcium handling
• Electrophysiological disturbances
• Impaired contractility and cardiac function^1,4

A recent study by Lees JG and colleagues used an FRDA iPSC-derived cardiomyocyte model to investigate the consequences of frataxin deficiency in human cardiac cells. The authors suggested that frataxin deficiency causes intrinsic cardiac abnormalities, including impaired contractility, prolonged contraction and relaxation times, irregular calcium handling, increased cardiomyocyte size, elevated mitochondrial reactive oxygen species (ROS), mitochondrial fragmentation, and enhanced cell death.

These phenotypes provide measurable endpoints for therapeutic evaluation, allowing researchers to assess both molecular and functional responses to candidate treatments in a disease-relevant cardiac model.¹

Enabling FRDA cardiac models through custom differentiation

As therapeutic programs become increasingly specialized, researchers require disease models aligned with specific biological questions. Access to patient-derived FRDA iPSC lines is an important starting point, but generating the appropriate cardiac cell type is often equally critical.

At Axol Bioscience, researchers can access a portfolio of FRDA patient-derived iPSC lines carrying FXN GAA repeat expansions and combine these with custom cardiomyocyte differentiation services. Depending on the research objective, FRDA lines can be differentiated into ventricular, left ventricular, or atrial cardiomyocytes, enabling the study of contractile dysfunction, calcium handling, electrophysiology, and chamber-specific disease phenotypes.

Researchers investigating hypertrophic remodeling and cardiomyopathy may benefit from ventricular cardiomyocytes, while chamber-specific populations can support studies of electrophysiological function and therapeutic response. Beyond differentiation, Axol supports manufacturing-scale cell production, cryopreservation, quality control, assay development, media optimization, phenotypic characterization, and integration with advanced in vitro platforms.

By combining patient-derived FRDA iPSC lines with custom cardiomyocyte differentiation and model development expertise, researchers can generate fit-for-purpose cardiac models tailored to target validation, therapy development, and translational research.

References

1. Lees JG, et al. Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia cardiomyocytes. Cell Death Dis. doi:10.1038/s41419-026-09030-3
2. Friedreich’s Ataxia Research Alliance (FARA). Clinical Management Guidelines for Friedreich Ataxia: The Heart and Cardiovascular System. 2022.
3. Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V, Martin AS. Heart disease in Friedreich’s ataxia. World J Cardiol. 2019;11(1):1-12. doi:10.4330/wjc.v11.i1.1
4. Monda E, Palmiero G, Rubino M, et al. Diagnosis and management of cardiovascular involvement in Friedreich ataxia. Heart Fail Clin. 2022;18(1):151-160. doi:10.1016/j.hfc.2021.07.012
5. Corben LA, et al. Friedreich’s ataxia: a rare multisystem disease. Lancet Neurol. 2025;24(7):614-624. doi:10.1016/S1474-4422(25)00175-9